15beta-fluorinated corticosteroids



United States Patent 3,056,808 156-FLUQRINATED CORTICGSTEROIDS Donald E. Ayer, Portage Township, Kalamazoo County, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Oct. 9, 1961, Ser. No. 143,557 Claims. (Cl. 260397.3)

This invention r elates to novel steroid compounds and processes for their preparation and is more particularly concerned with novel ISQ-fluorinated corticosteroids and with processes for their preparation.

The novel compounds of the invention can be represented by the following formula:

wherein the dotted line between carbon atoms 1 and 2 indicates that these carbon atoms are joined by a single or double bond, and wherein R is selected from the class consisting of hydrogen, hydroxy, and acyloxy, R represents hydroxy and, when R represents hydrogen, R also represents a group selected from the class consisting of hydrogen and acyloxy, X is selected from the class consisting of hydrogen and fluorine, Y is selected from the classfconsisting of hydrogen, fluorine and methyl, and Z is selected from the class consisting of fi-hydroxymethylene and carbonyl, and wherein the acyl of the acyloxy group in each instance is that of an organic carboxylic acid preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive.

The organic carboxylic acids, from which the acylates of the invention are derived, include saturated and unsaturated aliphatic acids and aromatic acids such as acetic, propionic, butyric, isobutyric, tert.-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic acrylic, crotonic, hexynoic, heptynoic, octynoic, cyclobutanecarboxylic, cyclopentanecarboxylic, cyclopentenecarboxylic, cyelohexanecarboxylic, dimethylcyclohexanecarboxylic, benzoic, toluic, naphthoic, ethylbenzoic, phenylacetic, naphthaleneacetic, phenylvaleric, cinnamic, phenylpropiolic, phenylpropionic, succinic, cyclopentylpropionic, a,a'- dimethylsuccinic, ,8,/i-dimethylglutaric acids, and the like.

The novel compounds of the invention having the Formula I above possess valuable physiological activity. Illustratively, the novel compounds of the Formula I possess glucocorticoid, mineralocorticoid and anti-inflammatory activity. The anti-inflammatory activity of the compounds of the invention is markely greater than that of the corresponding known compounds which lack the 155- fluoro group. In addition, the compounds of the invention possess the advantage that they exhibit much less sodium-retaining activity than the corresponding compounds which lack the ISB-fluoro group. Accordingly, the compounds having the Formula I above can be ad ministered to mammals and birds, particularly to humans and valuable domestic animals, for the treatment of various inflammatory conditions of the skin, eyes, respiratory tract and the bones and internal organs due to bacterial or viral infections, contact-dermatitis and allergic reactions, and rheumatoid arthritis.

The novel compounds of the invention having the Formula I also possess progestational activity and affect the secretion of gonadotropins and thus regulate ovulation and endometrial and placental development and, particularly when used in conjunction with estrogens, for example, ethinylestradiol, and with androgens, for example, Halotestin (9oZ-fluoro-1lB-hydroxy-17m methyltestosterone), reduce fertility, and constitute effective therapy for 'dysmenorrhea, amenorrhea, endometriosis, threatened abortion and related gynecological disorders in humans and valuable domestic animals.

The novel compounds of Formula I above also possess central nervous system depressant activity which makes them useful as sedatives and general anesthetics in mammals, particularly in humans and animals. For example, they can be used as sedatives and anesthetics in the laboratory manipulation of experimental animals such as mice and rats.

The novel compounds of Formula I can be prepared and administered in a wide variety of oral or parenteral dosage forms singly, or in admixture with other active compounds. They can be associated with a pharmaceutical carrier which can be solid material or a liquid in which the compound is dissolved, dispersed, or suspended. The solid compositions can take the form of tablets, powders, capsules, pills, or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups or elixirs.

The novel compounds of the invention can for the most part be prepared according to the following reaction scheme.

REACTION SCHEME A 17ahydmxy derivatives and A -analogues CH3 CH3 -OH r 2" (II) 3'? (III) i COzAlk 0 0mm ta 5H X [X A/ 3 Y v) i! av CHzO R" C HzOAc In the above formulae X and Y have the significance hereinbefore defined, Ac represents the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, R is selected from the class consisting of hydrogen and Ac, wherein Ac has the significance defined above, A represents an alkylen radical containing from 2 to 6 carbon atoms, inclusive, wherein the attaching oxygen to carbon bonds are separated by a chain of at least 2 and not more than 3 carbon atoms, and Alk is an alkyl radical containing from 1 to 8 carbon atoms, inclusive, such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, and octyl, and isomeric forms thereof.

The 21-deoxy-17-hydroxy compounds of the invention having the Formula I wherein R=H and R=hydroxy or acyloxy can also be prepared from the corresponding 17a,2l-dihydroxy compounds according to the following Reaction Scheme B:

REACTION SCHEME B CHzOH CHzOR if (XVIIl) Y (XVII) In the above formulae, X, Y, and Z have the significance hereinbefore defined and R represents an aryl or alkyl sulfonyl radical, preferably that of a hydrocarbon sulfonic acid containing from one to twelve carbon atoms, inclusive, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

The process of the invention shown diagrammatically in Reaction Scheme A is carried out in the following manner:

A 15u-hydroXy-1l-ketoprogesterone having the Formula II is subjected to fiuorination by treatment with a fluorinating agent having the formula:

wherein R and R taken individually represent lower alkyl and R and R taken together with the attached nitrogen atom rep-resent the residue of a heterocyclic radical containing from 5 to 7 ring atoms, inclusive, X is selected from the class consisting of chlorine and fluorine, and X is selected from the class consisting of chlorine, fluorine, and trifluo-romethyl in an inert organic solvent, and advantageously in the presence of an acid catalyst, whereby replacement of the lS-hydroxy by fluorine takes place accompanied by inversion to yield the corresponding 15 fi-fiuoro-l l-ketoprogesterone (HI) The term lower-alkyl employed above in defining the fluorinating agent means an alkyl radical containing from 1 to 8 carbon atoms, inclusive, such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl and isomeric forms thereof.

The term heterocyclic radical containing from 5 to 7 ring atoms, inclusive is inclusive of pyrrolidino, 2- methyl pyrrolidino, 2,2 dimethylpyrrolidino, and like alkylpyrrolidino groups, 4-methylpiperazino, 2,4-dimethylpiperazino and like 4-alkylpiperazino groups, morpholino, piperidino, Z-methylpiperidino, 3-methylpiperidino, and like alkylpiperidino groups, hexarnethyleneimino, homomorpholino, and the like.

Examples, of fluorinating agents which can be used in the above process are N-(2-chloro-1,l,2-trifluoroethyl)diethylamine, N-(1,1,2,2-tetrafiuoroethyl)diethylamine, N- (2-chloro-1,1,2-trifluoroethyl)dimethylamine, N- (2-chloro-l 1 ,Z-trifluoroethyl) dipropylamine, N-(2-chloro-l,1,2- trifluoroethyl)diisobutylamine, N-(2 chloro-l,1,2 trifluoroethyl)dioctylamine, N-(Z-chloro 1,1,2 trifluoroethyl)-methylethylamine, N-(1,l,2,2 tetrafluoroethyl)diisopropylamine, N-( 2,2-dichloro-1,1-difluoroethyl)diethylamine, N-(1,1,2,3,3,3 hexafluoropropyl)diethylamine, and the like. The preferred fluorinating agent for use in the above fluorination process is N-(2-chloro-l,1,2-trifluoroethyl) diethylamine.

The term inert organic solvent means any organic solvent which does not react with the fluorinating agent and in which the steroid starting material is appreciably soluble such as aromatic and aliphatic hydrocarbons, halogenated hydrocarbons, esters, ketones, ethers and tertiary alcohols. Examples of such solvents are benzene, toluene, chlorobenzene, pentanes, hexanes, cyclohexane, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, ethyl ether, t-butyl alcohol, t-amyl alcohol, and the like. Advantageously, the inert organic solvent employed in the above fluorination process is a halogenated aliphatic hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, ethylidene chloride, propylene chloride, trimethylene chloride, and the like. The solvent which is particularly preferred is methylene chloride.

Advantageously, but not necessarily, the process of the invention is carried out in the presence of an acid catalyst. The acid catalysts which are employed for this purpose are proton-forming acids such as the hydrogen halides, phosphoric acid, sulfuric acid, and the like or Lewis acids (see Fieser and Fieser, Organic Chemistry, third edition, page 138, Reinhold, 1956) such as boron trifiuoride, boron trichloride, aluminum trifluoride, arsenic trifluoride, phosphorus pentafiuoride, titanium tetrafluoride, and the like. The preferred acids are the hydrogen halides, particularly hydrogen fluoride. In the case of hydrogen fluoride, the acid can be added to the reaction mixture or can be generated in situ, for example, by addition of the requisite quantity of water or an aliphatic alcohol such as methanol, ethanol, and the like, to produce the desired quantity of hydrogen fluoride by reaction with the fluorinating agent as follows:

wherein R R X X have the significance hereinbefore described and R represents hydrogen or lower-alkyl.

In general the acid catalyst is present in the reaction mixture in catalytic quantities only, i.e. of the order of about 0.1 to about 25 percent of the starting hydroxy steroid on a mole equivalent basis.

The fluorination of the a-hydroxy-1l-oxoprogesterone (II) is carried out conveniently by bringing together the steroid (II), the fluorinating agent, and the acid catalyst in the presence of the inert organic solvent. The reaction is preferably carried out at a temperature Within the range of about 0 C. up to the boiling point of the reaction mixture. The reaction time employed to complete the fluorination varies according to the reaction temperature and is generally of the order of one to eighteen hours at temperatures of about 0 C. to about C. Shorter reaction times can be employed at higher reaction temperatures.

Advantageously the fluorinating agent is employed in excess of the stoichiometric quantity based on the steroid (II). Preferably the fluorinating agent is present in an excess of the order of about 1.1 to 10 moles per mole of starting steroid (II).

The desired lSfi-fluoro-ll-oxoprogesterone (III) so produced can be isolated from the reaction mixture and purified by conventional procedures, for example, by solvent extraction of the reaction product followed by removal of the solvent and recrystallization and/or chromatography of the resulting product.

The 15,8-fluoro-1l-oxoprogesterone (III) so obtained can be converted to the corresponding llB-hydroxy compounds using procedures known in the art. For example, the ll-oxo compounds are converted to the corresponding 3,20-bisketal derivatives, for example by reaction with an alkylene glycol such as ethylene glycol, the 11-oxo-3,20-bisketal so obtained is reduced using, for example, lithium aluminum hydride to give the corresponding 11fl-hydroxy-3,20-bisketal and the latter is then hydrolyzed to give the desired 1518-fluoro-11p-hydroxyprogesterone.

The compound (III) or the ISfl-fluoro-l lfl-hydroxyprogesterones obtained as described above can then be subjected to l7ot-hydroxylation by, for example, a microorganism of the genus Tr-ichothecium using procedures such as that described in U.S. Patent 2,925,366 to obtain the desired 15,8-fiuoro-1l-oxo-Nut-hydroxyprogesterones and 15f3-fluoro-l1,8,17u-dihydroxyprogesterones.

The ISB-fluoro-ll-oxoprogesterone (III), the 15pfluoro-1Iii-hydroxyprogesterones, the 15B-fluoro-11-oxo- 17a-hydroxyprogesterones, or the 15/3-fluor0-ll;8,17a-dihydroxyprogesterones obtained as described above can then be dehydrogenated using procedures known in the art to obtain the corresponding A -analogues. The l-dehydrogenation can be effected microbiologically using a l-dehydrogenation microorganism, for example, of the genus Septomyxa using procedures such as that described in U.S. Patent 2,897,218, or can be eflected chemically, for example, by treatment with selenium dioxide using procedures such as that described by Meystre et al., I-Ielv. Chim. Acta, 39, 734 (1956), or that described in British patent specification No. 864,414.

In the next stage of the process of Reaction Scheme A, the 15 6-fluoro-ll-oxoprogesterone (III) is converted to the Favorskii ester (IV) using conventional procedures. For example, the compound (III) is reacted with more than 2 molar equivalents each of sodium methoxide and an alkyl oxalate to produce the 2,21-digloxalate; the latter is tribrominated with bromine followed by rearrangement with sodium methoxide in methanol to produce the corresponding 2-br0mo-3,1=l-dioxo fluoro 4,17(20)- [cis]-pregnadien-2l-oic acid alkyl ester; and removing the bromine from the latter compound by treatment with reducing agents such as zinc and acetic acid, chromous chloride, and the like, to produce the Favorskii ester (IV). Alternatively the bromine can be removed by treatment with sodium iodide in acetone followed by reaction with the aforementioned reducing agents or collidine. The procedure employed in the above series of reactions is advantageously that described in U.S. Patent 2,790,814. The Favorskii ester (IV) is then converted to the corresponding 3-ketal (V) using, for example, the procedure described in U.S. Patents 2,707,184 or 2,758,- 993. Ethylene glycol is the preferred ketalizing agent but other glycols suitable for use include propylene-1,2-glycol, 2,2-dimethylpropylene-1,3-glycol and like lower alkylene glycols.

The 3-ketal (V) so obtained is reduced to the 3-ketal of the corresponding 3-oxo-lSB-fluoro-A:" -pregnadiene-llB,2l-di0l (VI). The reduction is effected using conventional procedures, for example, by treatment with lithium aluminum hydride in the presence of .an inert sol vent such as ether, tetrahydrofuran, and the like using procedures such as that described in U.S. Patent 2,695,- 906.

Acylation of the 21-hydroxy group of the compound (VI), for example, by reaction of the latter compound with the appropriate acid halide or acid .anhydride in the presence of a tertiary base such as pyridine, followed by deketalization for example, by hydrolysis with mineral acid, of the ZI-acylate of (VI) so obtained and oxidative hydroxylation of the 3-oxo-lSB-fiuoro-A -pregnadiene-llp,21-diol Zl-acylate so obtained, yields the corresponding ISfi-fluoro-I1p,17a,2l-trihydroxy-pregn-4-ene- 3,20-dione 2lacylate (VII). The oxidative hydroxylation is carried out by conventional procedures, for example, by treatment with osmium tetroxide and an oxidizing agent, for example, hydrogen peroxide or N-methylmorpholine oxide peroxide using procedures such as that described in US. Patents 2,769,823, 2,769,824, and 2,769,- 825.

The ZI-acylates (VII) can then be hydrolyzed to the corresponding free 21-alcohols, i.e. to the corresponding 15/3 fluoro 11fl,17oc,2l trihydroxypregn-4-ene 3,20- dione by hydrolysis using conventional procedures, for example, by treatment with a base such as sodium bicarbonate in solution in a lower alkanol such as methanol.

The 2l-acylates (VII) can also be oxidized, for example, by treatment with oxidizing agents such as chromic acid, sodium dichromate, and the like whereby the llfl-hydroxy group is oxidized and the corresponding 11- oxo compound (VIIA) is obtained. The latter compounds can be hydrolyzed to the corresponding free 21- hydroxy compounds using the procedure outlined above.

The compounds (VII) or (VIIA) or the corresponding free 21-hydroxy compounds can, if desired, be subjected to l-dehydrogenation using either microbiological or chemical means as described above, to yield the corresponding l-dehydro compounds (VIII). Where the 1- dehydrogenation is carried out using microbiological means a 2l-acylate in the starting compound (VII) r (VIIA) will generally be removed during the dehydrogenation. The resulting free 21-hydroxy compound (VIII; R=H) can be .acylated, if desired, by reaction with the appropriate acid halide or acid anhydride using the procedures described above.

The 15fl-fluoro-1153170 2l-trihydroxy-pregn-4-ene-3,20- dione 21-acylates (VII) wherein the radical X represents hydrogen can then be treated by conventional procedures, for example, those described in US. Patent 2,838,499, for the introduction of a 9oc-fil10r0 group. Thus the compounds (VII; X=H) can be subjected to 9,11-dehydration using conventional procedures, for example, treatment with an N-haloamide such as N-bromoacetamide followed by treatment with sulfur dioxide, to yield the corresponding A961) compound (IX).

The compound (IX) so obtained is then converted to the corresponding 9a-halo-llp-hydroxy-compound (X) by the addition of the appropriate hypohalous acid, i.e. hypochlorous, hypoiodous acid, or hypobromous acid for example by treatment with the appropriate N-haloacetamide or like N-haloamide. The 9zx-halo-llfi-hydroxy compound (X) so obtained is converted to the corresponding 9;3,11;3-epoxy compound (XI) by reaction with a mild base such as potassium acetate.

The epoxide (XI) is reacted with hydrogen fluoride or a hydrogen fluoride releasing agent, to produce the corresponding 9oc,15B-difluoro-1 1B,17a,21-trihydroxypregn-4- ene-3,20-dione 21-acylate (XII). The latter compound can be deacylated, if desired, using procedures hereinbefore described for the hydrolysis of 21-acylates, to obtain the corresponding free 21-hydroxy compounds.

The 9a,15,6 diflu0ro-11,8,l7u,21-trihydroxypregn-4-ene- 3,20-dione-21-acylates (XII) can be oxidized using chromic acid, sodium dichromate and like oxidizing agents to obtain the corresponding 9a,15fi-difluoro-17a,21-dihydroxy-pregn-4-ene-3,1l20-dione 21-acy1ates (XIII). The latter compounds can be hydrolyzed to the corresponding free 21-hydroxy compounds using the procedures described above. Both the compounds (X11 and XIII) can be subjected to l-dehydrogenation using either microbiological or chemical means as hereinbefore described to yield the corresponding l-dehydro compounds (XIV). Where the l-dehydrogenation is carried out by microbiological processes any 2 1-acyl group present in the starting materials will generally be eliminated during the reaction. The 21-free alcohols (XIV; R=H) can be acylated by reaction withthe appropriate acid halide or acid .anhydride using procedures described above to obtain the corresponding 2l-acylates (XIV: R=Ac).

The 21-deoxy-17a-hydroxy compounds of the invention (1; R=H; R =hydroxy or acyloxy) can also be prepared using the sequence of reactions shown in Reaction Scheme B as follows: The compounds (VII), (VIIA), (VIII), (XII), (XIII), or (XIV), [represented generically as compound (XV) in Reaction Scheme B] are hydrolyzed, where necessary, to the corresponding free 2l-alcohols and the latter are reacted with an organic sulfonyl halide such as methanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonyl bromide, benzenesulfonyl chloride, naphthalenesulfonyl chloride, and the like, in the presence of a tertiary base such as pyridine, to obtain the corresponding 21sulfonate esters (XVI).

The 21-sulfonate esters (XVI) so obtained are converted to the corresponding 2l-iodo compounds (XVII) by reaction with an alkali metal iodide, such as sodium iodide, potassium iodide, and the like, in the presence of a suitable solvent, for example an alkanone such as acetone, methyl ethyl ketone, and the like.

The 21-iodo compounds (XVII) are reacted with a reducing agent such as hydrogen iodide in acetic acid, zinc and acetic acid, chromous chloride, and the like, whereby the corresponding 21-deoxy compounds (XVIII) are obtained. Where the group Z in the 21-deoxy compound (XVIII) represents hydroxyl, said compound can be converted to the corresponding 11-oxo compound by reaction with an oxidizing agent such as chromic acid, sodium dichromate, N-bromoacetamide, N-bomosuccinimide, and the like, using conditions hereinbefore described.

The 2l-deoxy compounds (XVIII) can be converted to the corresponding 17-acylates by reaction with the appropriate acid anhydride in the presence of an acid catalyst such as p-toluenesulfonic acid or a basic catalyst such as calcium carbonate. The 15a-hydroxy-1l-oxoprogesterones (II) which are employed as starting materials in the process of the invention can be prepared from the corresponding ll-oxoprogesterones by subjecting the latter to the action of a 15a-hydroxylating microorganism such as Penicilliumurticae using the procedures set forth in the following preparations.

The following preparations and examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

PREPARATION 1 15a-Hydr0xy-11 -Ox0pr0gester0ne A medium was prepared of 10 g. of Cerelose (dextrose), 20 g. of corn steep liquor and 1 liter of water and adjusted to a pH between 5.5 and 6. A 12 liter portion of this sterilized medium was inoculated with spores of Penicillium urticae ATCC 10120 and incubated for a period of 24 hours at a temperature of 26 C. using a rate of aeration and stirring such that the oxygen uptake was 13 millimoles per hour per liter [estimated according to the method of Cooper et al., Ind. Eng. Chem. 36, 504 1944)]. To this medium containing a 24-hour growth of Penicillium urticae was added 2 g. of 11-oxoprogesterone, dissolved in ml. of acetone. The mixture so obtained was incubated for a further 24 hours under the same temperature and aeration conditions before being harvested and clarified. The mycelium was Washed twice with a roughly equal volume of acetone and was then extracted twice with an equal volume of methylene chloride. The acetone and methylene chloride extracts were added to the beer filtrate and the combined extracts and beer filtrate were extracted successively with two one-half by volume portions of methylene chloride and then with two one-fourth by volume portions of methylene chloride. The methylene chloride extracts were combined and washed with aqueous sodium bicarbonate solution and then with Water. The Washed extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness and the residue was chromatographed on a column of magnesium silicate (Florisil). The column was eluted with Skelysolve B containing increasing proportions of acetone and those fractions which, on the basis of infrared analysis, were shown to contain the desired product were combined and evaporated to dryness. The residue was recrystallized twice from a mixture of acetone and ether and then once from a mixture of acetone and Skellysolve B. There was thus obtained 15a-hydroxy-1l-oxoprogesterone in the form of a crystalline solid having a melting point of 227 to 229 C.; [111 +257 (ethanol).

PREPARATION 2 15a-Hydr0xy -6a-Methyl-1 1 -Oxpr0gester0ne Using the procedure described in Preparation 1, but replacing ll-oxoprogesterone by 6a-methyl-11-oxoprogesterone (US. 2,968,655), there is obtained 15a-hydr0xy-6ct-methyl-l l-oxoprogesterone.

PREPARATION 3 15a-Hydr0xy -6oc-Flu0r0-1 1 -Ox0 progesterone Using the procedure described in Preparation 1, but replacing ll-oxoprogesterone by 6m-fluoro-11-oxoprogesterone (U.S. 2,838,501), there is obtained 15a-hydroxy-6ot-fluoro-1 l-oxoprogesterone.

PREPARATION 4 15a-Hydroxy-6a,9a -Diflu0r0-1 1 -Ox0 progesterone Using the procedure described in Preparation 1, but replacing ll-oxoprogesterone by 6a,9o-diflu0ro-ll-oxoprogesterone (US. 2,838,501), there is obtained l5oc-hydroxy-6a,9a-difiuoro-1 l-oxoprogesterone.

PREPARATION 5 1 5 u-Hydroxy -9u-Flu0r0-1 1 -0x0 progesterone Using the procedure described in Preparation 1, but replacing 11 oxoprogesterone by 9oc-fill0IO-11-OXOPIO- gesterone [3. Fried et al., J. Am. Chem. Soc., 77, 1068 (1955)], there is obtained 15a-hydroxy-9wfluoro-11-oxoprogesterone.

PREPARATION 6 15a-Hydr0xy-6a -Methyl-9a-Flu0r0-1 1 -Ox0 progesterone Using the procedure described in Preparation 1, but replacing ll-oxoprogesterone by 6a-rnethyl-9u-fluoro-1loxoprogesterone (US. 2,968,655), there is obtained 150chydroxy-6a-methyl-9a-fluoro-1 l-oxoprogesterone.

EXAMPLE 1 15,8-Flu0r0pregn-4-Ene-3,1 1 ,2 0- Trione A solution of g. (0.029 mole) of a-hydroxy-11- oxoprogesterone in 300 ml. of methylene chloride was cooled to 5 C. with exclusion of moisture and 9 ml. (10.7 g.; 0.0564 mole) of N-(2-chloro-1,1,2-trifluoroethyl) diethylamine was added. The resulting mixture was allowed to stand for 4.5 hours at 5 C. before ice water was added. The organic layer was separated, washed successively with water, aqueous sodium bicarbonate solution, and water before being dried over anhydrous magnesium sulfate. The dried solution was filtered and the filtrate was distilled initially at atmospheric pressure to remove solvent and finally at 90 C. under a pressure of 1 mm. of mercury to remove residual N,N- diethylchlorofluoroacetamide. The oily distillation residue was dissolved in methylene chloride and chromatographed on a column of magnesium silicate (Florisil).

The column was eluted with 4 l. of mixed hexanes (Skellysolve B) containing 12.5% by volume of acetone. The first 4 l. of eluate was evaporated to dryness to yield 1.98 g. of pregna-4,14-diene-3,11,20-trione in the form of a crystalline solid having a melting point of 193 to 196 C. The next 3 l. of eluate was evaporated to give 1.59 g. of a mixture containing 2 parts of l5fl-fluoropregn-4-ene-3, 11,20-trione, 1 part of pregna-4,14-diene-3,11,20-trione, and 1 part of the l5-chlorofluoroacetate of 15a-hydroxypregn-4-ene-3,11,20-trione. The column was then eluted with Skellysolve B containing increased proportions of acetone up to 30% by volume. The next 4.5 l. of eluate was evaporated to obtain 2.28 g. of 15/3-fiuoropregn-4- ene-3,11,20-trione in the form of a crystalline solid having a melting point of 157 to 159 C. Later fractions of eluate yielded a further 1.7 g. of impure lSB-fluoropregn- 4-ene-3,11,20-trione which was combined with the earlier impure fraction and rechromatographed under similar solvent conditions to obtain an additional 1.9 g. of product (total yield of l5fi-fiuoropregn-4-ene-3,11,20-trione= 42%). An analytical sample of 15fl-fluoropregn-4-ene- 3,11,20-trione having a melting point of 159 to 161 C. was obtained by recrystallization from a mixture of acetone and Skellysolve B. The ultraviolet spectrum of this compound (in ethanol) exhibited a maximum at 237.5 millimicrons (E=l4,300).

Analysis.Calcd. for C H 7O 'F: C, 72.80; H, 7.86; F, 5.48. Found: C, 73.42; H, 7.64; F, 5.20.

Using the above procedure, but replacing ISa-hYdIOXY- l1 oxoprogesterone by 15a-hydroxy-6u-methyl-1l-oxoprogesterone, 15a hydroxy 6a fiuoro-ll-oxoprogesterone, 150a hydroxy 60,9u difluoro-ll-oxoprogesterone, 15a hydroxy c fiuoro-ll-oxoprogesterone, or 15a hydroxy 60c methyl9a-fiuoro-1l-oxoprogesterone, there are obtained 15,8 fiuoro 6a methyl-11- oxoprogesterone, 611,155 difluoro-ll-oxoprogesterone, 6u,9u,155 trifluoro 11 oxoprogesterone, 9a,15B-difiuoro-ll-oxoprogesterone, and 60: methyl 90t,15[8-dl fluoro-l l-oxoprogesterone, respectively.

EXAMPLE 2 15,6-Flu*oro1 1fl-Hydroxypregn-4-iEne3,20-Dione A mixture of 1 g. of 156-fluoropregn-4-ene-3J1,20-trione, 0.06 g. of p-toluenesulfonic acid, 5 ml. of ethylene glycol, and ml. of benzene is stirred and heated under reflux. The water formed in the reaction is collected in a water trap. When the elimination of water is complete, the reaction mixture is cooled, washed with aqueous sodium bicarbonate solution, and then with water, and dried over anhydrous sodium sulfate. The dried solution is filtered, the filtrate is evaporated to dryness, and the residue is recrystallized from ethyl acetate.

A slurry of 1 g. of the 3,20-bisethylene ketal of 15,8- fiuoropregn-4-ene-3,11,20-trione so obtained in 20 ml. of benzene is added to a slurry of 0.35 g. of lithium aluminum hydride in 100 ml. of anhydrous ether at such a rate as to cause gentle refluxing. When the addition is complete, the reaction mixture is heated under reflux to complete the reaction and is then cooled and hydrolyzed with Water. The organic layer is separated, washed with water, and dried over anhydrous sodium sulfate. The dried solution is filtered, the filtrate is evaporated to dryness, and the residue is recrystallized from ethyl acetate.

A mixture of 0.5 g. of the 3,20-bisethylene ketal of 15,8- fiuoro 11;? hydroxypregn 4-ene-3,20-dione so obtained, 20 ml. of acetone and 5 ml. of 3 N hydrochloric acid is heated under reflux for several hours before being diluted with water. The solid which separates is isolated by filtration and dried. There is thus obtained 15,8-fluoro-11B- hydroxypregn-4-ene-3,20-dione in the form of a crystalline solid.

Using the above procedure, but replacing 15,8-f1uoropregn 4 ene 3,11,20-trione by 15,8-fluoro-6a-methylpregn 4-ene-3,11,20-trione, 6a,15fi-difiuoropregn-4-ene- 3,11,20 trione, 6a,9u,15p-trifluoropregn-4-ene-3,11,20-

trione, 9a,15fl-difluoropregn-4-ene-3,11,20-trione, or 9a, 155 difluoro-6a-methylpregn-4-ene-3,11,20-trione, there are obtained 15,8 fluoro 11/3 hydnoxy-6a-methylpregn- 4 ene 3,20-dione, 6orl5l3-difiuoro-l1fi-hydroxypregn-4- ene 3,20 dione, 6a,9a,15t3 trifiuoro-llB-hydroxypregn 4 ene 3,20-dione, 9a,15,8-difluoro-1lB-hydroxypregn 4 ene 3,20-dione, and 9u,l5fl-difluoro-11,B-hydroxy-6u-methylpregn-4-ene,3,20-dione, respectively.

EXAMPLE 3 1 SB-Fluoropregna-l ,4 -D iene-3,1 1 ,ZO-Trione A mixture of 0.5 g. of l5B-fiuoropregn-4-ene-3,l1,20- trione, 50 m1. of t-butyl alcohol, 0.5 ml. of acetic acid and 0.2 g. of selenium dioxide is heated under reflux for 48 hrs. At the end of this time an additional quantity of 0.2 g. of selenium dioxide is added and the heating is continued for approximately 20 hrs. The resulting mixture is then filtered and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and the solution so obtained is washed successively with cold aqueous sodium bicarbonate solution, aqueous ammonium polysulfide solution, aqueous ammonium hydroxide solution, water, dilute hydrochloric acid, and water. The washed solution is evaporated to dryness and the residue is dissolved in methylene chloride and chromatographed on a magnesium silicate (Florisil) column. The column is eluted with methylene chloride containing increasing proportions of acetone and those fractions which, on the basis of infrared analysis, are shown to contain the desired 15,8- fiuoropregna-l,4-diene-3,1l,20-trione are combined and evaporated to dryness. The residue is recrystallized from aqueous acetone. There is thus obtained 15,8-fluoropregna-1,4-diene-3,l1,20-trione in the form of a crystalline solid.

Using the procedure described above, but replacing 15 B-fluoropregn-4-ene-3,1 1,20-trione by 15 fi-fluoro-6a-methyl-l l-oxoprogesterone,

9a,l5,6-difluoro-1 l-oxoprogesterone,

6a-methyl-9a, 15 B-difluoro-l l-oxoprogesterone,

15/8-fluoro-1 l B-hydroxypregn-4-ene3,20-dione,

ISB-fiuoro-l lB-hydroxy-6ot-methylpregn-4-ene-3,20-

dione,

601,15 ,B-difluoro-l l B-hydroxypregn-4-ene-3,20 dione,

6a,9a,15B-triflUOrO-1 1fi-hydroxypregn-4-ene-3 ,20-dione,

there are obtained 15 B-fluoro-6a-methylpregna-1,4-diene-3,1 1,20-trione,

60,15 fl-difluoropregna-1,4-diene-3,1 1,20-trione,

9zx,l5,6-difiuoropregna-1,4-diene-3,l 1,20-trione,

9oz,15,8-difluoro-6a-methylpregna-1,4-diene-3,l1,20-

trione,

ISB-fluoro-l 1fl-hydroxypregna-1,4-diene-3,20 dione,

15 B-fiuoro-l 1 ,8-hydroxy-6a-methylpregna-1,4-diene- 3,20-dione,

60:,15fi-difi1101'0-1 lB-hydroxypregna-l ,4-diene-3,20'-

dione,

6a,9a,15,8-trifluoro-1 1 ,B-hydroxypregna-1,4-diene-3 ,20-

dione,

respectively.

EXAMPLE 4 Methyl 3,11-Di0x0-15,B-Flu0r0-4,1 7(20) [Cis] Pregnadien-ZI -Oate To a stirred, nitrogen-purged solution of 2.42 g. (0.007 mole) of l55-fluoropregn-4'ene-3J1,20-trione in 50 ml.

of t-butyl alcohol at 60 C. was added 3.8 ml. (4.08 g., 0.028 mole) of ethyl oxalate followed by 3.9 g. (0.0175 mole) of 24.3% methanolic sodium methoxide. The resulting mixture was stirred for 45 minutes after the addition was complete and was then cooled and neutralized by the addition of 1 ml. of acetic acid and 0.85 g. of sodium acetate in 25 ml. of methanol. The neutral mixture was cooled to 0 C. and a solution of 3.36 g. (0.021 mole) of bromine in 10 ml. of methanol at minus 30 C. was added dropwise thereto over a period of 5 minutes. To the mixture so obtained was added 8.55 g. (0.0385 mole) of a 24.3% methanolic solution of sodium methoxide over a short period keeping th temperature below 15 C. The resulting mixture was warmed to 25 C. and tirred for 1 hour, after which 3 ml. of acetic acid and 2.4 g. of zinc dust was added and the mixture was stirred for a further 30 minutes. The reaction mixture was then filtered through diatomaceous earth (Celite) and the filtrate was evaporated to a small volume. The residue was dissolved in methylene chloride and washed successively with water, aqueous sodium bicarbonate solution, and water. The washed solution was evaporated to dryness and the residue was dissolved in methylene chloride and chromatographed on a column of magnesium silicate (Florisil). The column was eluted with Skellysolve B containing 12.5% by volume of acetone and those fractions which were found by paper chromatographic analysis to contain the desired material were combined and evaporated to dryness. The residue (1.52 g.) wa recrystallized from a mixture of acetone and Skellysolve B. There was thus obtained 0.58 g. of methyl 3,11-oxo-15pfluoro-4,17(20)-[cis]-pregnadiene-21-oate in the form of a crystalline solid having a melting point of 220 to 222 C. The ultra-violet spectrum of the compound (ethanol solution) exhibited a maximum at 231 millimicrons (E=23,200). The infrared spectrum of th compound (mineral oil mull) exhibited maxima at 1720, 1700, 1675, 1660, and 1620 reciprocal centimeters.

Analysis.Calcd. for C22H27O4FI C, 70.56; H, 7.27; F, 5.07. Found: C, 70.15; H, 7.38; F, 5.09.

Using the above procedure, but replacing lSfi-fluoropregn-4-ene-3,11,20-trione as starting material by 15 B-fiuoro-6a-methyl-1 l-oxoprogesterone, 604,153-(111111010-11-OXOPIOg6StflIOI16, 6a,90 ,15fi-[r1flllOIO-1 l-oxoprogesterone, or 6u-methyl9 x,15,8-difluoro-l l-oxoprogesterone, there are obtained methyl 3,11-dioxo-15[3-fluoro-6u-methyl-4,17(20)- [cis] -pregnadiene-21-oate, methyl 3,11-dioxo-6a,15fi-difluoro-4,17(20)-[cis]- pregnadiene-Zl-oate, methyl 3,1l-dioxo-6ot,9a,15,6-trifluoro-4,17(20)-[cis]- pregnadiene-Zl-oate, methyl 3,1 l-dlOXO-9OL, 15 ,8-difluoro-4,17 20) [cis] pregnadiene-Zl-oate, and methyl 3,11-dioxo-6u-methyl-9ot,15,B-difluoro-4,17(20)- [cis] -pregnadiene-21-oate,

respectively.

EXAMPLE 5 15 6-Flu0r0-1 15,1 70,21-Trihydroxypregn-4-Ene 3 ,ZO-Dione 21 Acetate A mixture of 2.59 g. of methyl 3,11-dioxo-155-fluoro- 4,17(20)-[cis]-pregnadien-21-oate, 150 mg. of p-toluenesulfonic acid monohydrate, and 5 ml. of ethylene glycol in ml. of benzene wa heated under reflux with stirring and azeotropic distillation of water until no further water was eliminated from the reaction mixture. The reaction mixture was then cooled to about 40 C., 0.4 ml. of pyridine was added and the mixture was cooled to room temperature. The benzene layer was separated, washed with water and dried over anhydrous magnesium sulfate.

The dried solution was filtered and the filtrate was evaporated to dryness. The residue was recrystallized 13 from a mixture of ethyl acetate and Skellysolve B. There was thus obtained the 3-ethylene ketal of methyl 3,11- dioxo-lB-fluoro-4,17(20)-[cis]-pregnadien-Zl-oate in the form of a crystalline solid having a melting point of 203 to 205 C.

A solution of 3 g. of the above 3-ethylene ketal in 30 ml. of benzene was added to a mixture of 1 g. of lithium aluminum hydride and 75 ml. of ether which had previously been stirred for 2 hr. at room temperature. The resulting mixture was stirred for 1 hr. at room temperature before the excess hydride was decomposed by the addition ofethyl acetate and water. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was evaporated to dryness under reduced pressure. The residue (ll-ethylene ketal of 115, 21 dihydroxy 15,6 fluoro-4,17(20)-[cis]-pregnadien-3- one) was dissolved in 4 ml. of pyridine and 8 ml. of acetic anhydride and was allowed to stand at room temperature for 18 hr. The resulting mixture was decomposed by pouring onto ice and water and the solid which separated was isolated by filtration and washed with water.

The washed solid (3-ethylene ketal of 11,8,21-dihydroxy B fluoro 4,17()-[cis]-pregnadien-El-one 21- acetate) was dissolved in a mixture of 100 m1. of acetone and 10 ml. of 5% sulfuric acid and allowed to stand for 20 hrs. at room temperature before adding 40 m1. of 4% sodium bicarbonate solution and evaporating the resulting mixture to a small volume. The residue was extracted with methylene chloride. The methylene chloride extract was washed with aqueous sodium bicarbonate solution and water before being evaporated to dryness. The residue was dissolved in methylene chloride and chromatographed on a column of magnesium silicate (Florisil). The column was eluted with Skellysolve B containing 12.5% by volume of acetone. Those fractions of the eluate which were found by paper chromatographic analysis to contain the desired product were combined and evaporated to dryness. There was thus obtained l15,21-dihydroxy-l5B-fiuoro-4,17(20) [cis] pregnadien-3-one 2l-acetate in the form of a crystalline solid.

A mixture of 1.93 g. of the latter compound, 106 ml. of t-butyl alcohol, 0.6 ml. of pyridine, 12 mg. of osmium tetroxide and 6 ml. (2.75 mol. eq.) of N-methylmorpholine oxide hydroperoxide in t-butanol was allowed to stand at room temperature under a nitrogen atmosphere for 21 hr. To the resulting mixture was then added a solution of 0.25 g. of sodium hydrosulfite in 50 ml. of water and the mixture was stirred for 30 minutes before being evaporated to a small volume. The residue was extracted with ethyl acetate and the extract was washed successively with Water, aqueous sodium bicarbonate solution, and water. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was dissolved in methylene chloride and chromatographed on a column of magnesium silicate (Florisil). The column was eluted with Skellysolve B containing increasing portions of acetone and those fractions which were found by paper chromatographic analysis to contain the desired product were combined and evaporated to dryness. The residue was recrystallized from aqueous methanol. There was thus obtained 0.63 g. of 15B-fluoro-11fi,17a,21-trihydroxypregn-4-ene-3,20-dione 21-acetate in the form of a crystalline solid having a melting point-of 206 to 208 C. with decomposition.

An analytical sample having a melting point of 210 to 211 C., with decomposition, was obtained by further recrystallization from aqueous methanol. The ultraviolet spectrum of this compound (ethanol solution) exhibited a maximum at 241 millimicrons. The infrared spectrum of this compound (mineral oil mull) exhibited maxima at 3580, 3360, 1730, 1715, 1662, 1630, 1620 (sh.), 1595, 1265, and 1245 reciprocal centimeters.

Analysis.Calcd. for C H FO .%H O: C, 64.96; H 7.44; F, 4.45. Found: C, 64.54; H, 7.68; F, 4.41.

On drying under high vacuum at 115 C., there is obtained the anhydrous material.

Using the procedure described above, but replacing methyl 3, 1 1-dioxo-15fl-fluoro-4, 17( 20) [cis] -pregnadien- 21-oate by methyl 3,11-dioxo-15/3-fluoro-6u-methyl-4,17- (20)-[cis]-pregnadien-21-oate, methyl 3,l1-diOXO-6o,15fidifluoro-4,17(20)-[cis]-pregnadien-21-oate, methyl 3,11- dioxo 6a,90c,15fi trifluoro-4,17( 20)-[cis1-pregnadien-21- oate, methyl 3,11-dioxo-9a,15fl-difluoro-4,17(20)-[cis]- pregnadien-Zl-oate, or methyl 3,11-dioxo-6a-methyl-9a,- 15B-difluoro-4,17(20)-[cis] -pregnadiene-21-oate, there are obtained 15 ,8 fluoro-6ot-methyl 11/3,17a,21 trihydroxypregn-4-ene-3,20-dione 21-acetate, 6a,15/3-difluoro-11,B,- 17a,21-trihydroxypregn-4-ene-3,20-dione 21-acetate, 6a,- 9a,15 3-trifiuoro 11,8,17a,21 trihydroxypregn-4-ene-3,20- dione 21-acetate, 9a,15/3-difluoro-11fl,17o,21-trihydroxypregn-4-ene-3,20-dione 21-acetate, and 6amethyl-9ot,15 8- difluoro-l1,8,17u,21-trihydroxypregn-4-ene-3,20-dione 21- acetate, respectively.

EXAMPLE 6 ISfl-Fluoro-l 1 5,1 704,21-Trihydr0xypregn-4-Ene- 3,20-Di0ne A mixture of 1 g. of ISB-fiuoro-l1B,17a,21-trihydroxypregn-4-ene-3,20-dione 21-acetate, 1 g. of potassium bicarbonate, ml. of methanol and 15 ml. of Water is purged with nitrogen and maintained at room temperature for several hours with stirring. The solution so obtained is neutralized by the addition of acetic acid and then distilled under reduced pressure to remove the methanol. The residue is extracted with methylene chloride and the extract is dried over anhydrous sodium sulfate. The dried solution is filtered and the filtrate is evaporated to dryness. There is thus obtained ISB-fluoro- 11B,1711,21-trihydroxypregn-4-ene-3,20-dione.

Using the above procedure 15fi-fluoro-6oc-methyl-115,- 17a,21-trihydroxypregn-4-ene-3,20-dione, 6a,15[3-difiuoro 115,170:,21-trihydroxypregn-4-ene-3,20-dione, 6a,9oc,l5}3- trifluoro 11B,17oz,21 trihydroxypregn-4-ene-3,20 dione, 9u,15,6-difluoro 11B,l70c,21 trihydroxypregn-4-ene-3,20- dione, and 6a-methyl-9a,ISB-difluoro-11(3,17u,21-trihydroxypregn-4-ene-3,20-dione were obtained by hydrolysis of the corresponding 21-acetates.

EXAMPLE 7 1 5 fi-F luoro-l 1 [1,] 704,21 -Trihydr0xypregn-4-Ene- 3,20-Dione 21 -Pr0pi0nate A solution of 1 g. of 15,8-fiuoro-11,8,17a,21-trihydroxypregn-4-ene-3,20-dione in 10 ml. of pyridine and 10 ml. of propionic anhydride is allowed to stand for several hours at room temperature before being poured into water. The solid which separates is isolated by filtration, washed with water and recrystallized from aqueous methanol. There is thus obtained 15fl-fluoro-11 8,17u,21- trihydroxypregn-4-ene-3,20-dione 21-propionate in the form of a crystalline solid.

In like manner, but replacing propionic anhydride by the appropriate hydrocarbon carboxylic acid anhydride, or acid halide, there are prepared other 21-esters of 15,5- fluoro 1118,17a,21-trihydroxypregn-4-ene-3,20-dione such as the 21-trimethylacetate, 21-butyrate, 21-hexanoate, 21,8- cycl-opentylpropionate, 21-hemisuccinate, 21-glutarate, 21- fi e-dimethylglutarate, 21-benzoate, 21-phenylacetate, and the like.

In like manner by reacting any of the compounds named in the paragraph following Example 6 with the appropriate acid anhydride or acid halide there is obtained the corresponding 21-acylate.

EXAMPLE 8 15B-Flu0ro-1 70,21-Dihydr0xypregn-4-Ene- 3,11,20-Tri0ne ZJ-Acetate A solution containing 0.1 g. of 15fl-fiuoro-11p,17a,21-

15 trihydroxypregn-4-ene-3,20-di0ne 2l-acetate, 1 ml. of acetic acid, 20 mg. of chromic anhydride and 1 drop of water is shaken and allowed to stand for several hours at room temperature. Thereafter the solution is poured into water and the solid which separates is isolated by filtration, Washed with Water, and dried. There is thus obtained 155 fluoro 17a,21-dihydroxypregn-4-ene-3,l1,20-trione 21-acetate.

Using the above procedure, but replacing 155-fluoro- 115,17u,21 trihydroxypregn 4 ene 3,20 dione 21- acetate by l55-fluoro-6a-methyl-1l5,17a,2l-trihydroxypregn 4 ene 3,20 dione 21 -acetate, 6a,155 difluoro- 115,17u,21 trihydroxypregn 4 ene 3,20 dione, 21 acetate, 60:,9a155 trifiuoro 11/3,17cc,21 trihydroxypregn 4 ene 3,20 dione 21 acetate, 90,l55- difluoro-115,l7ot,21 trihydroxypregn 4 ene 3,20- dione v2l-acetate, or 6u-methyl-9a,l55-difiuoro-115,17u, 21 tr-ihydroxypregn 4 ene 3,20 dione 2l-acetate, there are obtained 155 fluoro 60c methyl 170:,21- dihydroxypregn 4 ene 3,11,20 trione 21 acetate, 60c, 155 difluoro 17oc,2l dihydroxypregn 4 ene 3, 11,20 trione 21 acetate, 6ot,9u,155 trifiuoro 17a,21- .dihydroxypregn 4 ene 3,11,20 trione ZI-acetate, 9a, 155 difluoro 1704,21-dlhYClI'OXYPIBgH 4 ene 3,11,20- trione 21 acetate, and 6ot-methyl-9a,l55-difluoro-l7ec,21- dihydroxypregn 4 ene 3,11,20 trione .21-a-cetate, re spectively.

The 21-acetates obtained as described above can be converted to the corresponding free 21-hydroxy compounds using the procedure described in Example 6. The free 21-hydroxy compounds can be converted to other 2l-acylates by reaction with the appropriate acid anhydride or acid halide using the procedure described in Example 7.

EXAMPLE 9 155-Flu0r0-115J 70;,21-Trihydr0xy-1,4-Pregnadiene 3,20-Dione 21 Acetate Using the procedure described in Example 3, but replacing 155 fluoropregn 4 ene 3,11,20 -trione by 155 fluoro 115,17a,2l -trihydroxypregn 4 ene 3,20- dione 21-acetate, there is obtained 155 fluoro 115,17oc, 21 trihydroxy 1,4 pregnadiene 3,20 dione 21- acetate.

Similarly, using the procedure described in Example 3 but replacing 155 fluoropregn 4 ene 3,11,20 trione by 155 fluoro 17oc,2l dihydroxypregn 4 ene- 3,11,20 trione 2l-acetate, 155 fluoro 6a -methy-l 11b, 17a,21 trihydroxypregn 4 ene 3,20 dione 21-acetate, 155 fluoro 60 methyl 1711,21 dihydroxypregn- 4 ene 3,11,20 trione 21-acetate, 60:,155 difluoro 115, 1711,21 trihydroxypregn 4 ene 3,20 dione 21-acetate, 60:,155 difluoro 17oc,21 dihydroxypregn 4 ene- 3,1l,20 trione 21-acetate, 6a,9a,155 trifiuoro 115,17a, 21 trihydroxypregn 4 ene 3,20 dione 21-acetate, 6a,9a,155 trifiuoro 170;,21 dihydroxypregn 4 ene- 3,11,20 trione 21-acetate, 90:,155 difluoro 1711,21- dihydroxy-pregn 4 ene 3,11,210 trione 2l-acetate, 6amethyl 90,155 difluoro 115,17u,21 trihydroxypregn- 4 ene 3,20 dione 21-acetate, or 61 methyl 9a,155- difluoro 17oz,21 dihydroxypregn 4 ene 3,11,20- trione ZI-acetate there are obtained 155 fluoro 170:,21- dihydroxy 1,4 pregnadiene 3,11,20 trione 2l-acetate, 155 fluoro 6a methyl 1l5,l7u,21 trihydroxy 1,4- pregnadiene 3,20 dione 21-acetate, 155 fluoro 6amethyl 170:,21 dihydroxy 1,4 pregnadiene 3,11,20- trione 21-acetate, 6a,155 difluoro 11,6,170L,21 trihydroxy 1,4 pregnadiene 3,20 dione 2l-acetate, 60,155- difluoro 17oc,21 dihydroxy 1,4 pregnadiene 3,11,20- trione 21-acetate, 60c, 9a,155 trifiuoro 115,l7 x,21 trihydroxy 1,4 pregnadiene 3,20 dione 21-acetate, 6oz, 9a,155 trifiuoro 170:,21 dihydroxy 1,4 pregnadiene 3,11,20 trione 21 acetate, 911,155 difluoro- 17OL,Z1 dihydroxy 1,4 pregnadiene 3,11,20 trione l 6 21-acetate, 6oz methyl ,155 difluoro 11B,17a,21- trihy-droxy 1,4 pregnadiene 3,210 dione 2l-acetate, and 6a methyl 904,155 difluoro 17a,21 dihydroxy- 1,4 pregnadiene 3,11,20 tr-ione 2l-acetate, respectively. The aforementioned compounds can be converted to the corresponding free 2l-hydroxy compounds using the procedure described in Example 6. The free 2l-alcohols so obtained can be converted to the corresponding 21- acylates by reaction with the appropriate acid anhydride or acid halide using the procedure described in Example 7.

EXAMPLE 10 -Flubro-1 7a,21-Dihyar0xy-95,1 15-0xid0pregn- 4-Ene-3,2 O-Dione 21 -Acetate To a solution of 0.7 g. of 155-fluoro-115,17u,21-trihydroxypregn 4 ene 3,20 dione ZI-acetate in 15 ml. of pyridine was added 0.38 g. of N-bromoacetamide. The mixture was stirred under an atmosphere of nitrogen for 20 minutes at 25 C. and then cooled to 10 C. Sulfur dioxide was passed over the surface of the cooled solution for 15 minutes after which the reaction mixture was diluted with ice water. The solid which separated Was isolated by filtration, washed with Water and dried. The 155 fluoro :,21 dihydroxy 4,9(11) pregnadiene 3,20 dione 21-acetate (0.53 g.) so obtained was dissolved in a mixture of 10 ml. of methylene chloride and 18 ml. of t-butyl alcohol. To this solution was added 0.16 ml. of 70% perchloric acid in 1.25 ml. of water, and 0.25 g. of N-bromoacetamide in 2.5 ml. of tbutyl alcohol. The mixture was stirred for 15 minutes at 25 to 30 C. and 0.25 g. of sodium white in 2.5 ml. of water was added. The resulting solution was concentrated under reduced pressure and the residue was diluted with ice water. The solid which separated was isolated by filtration, washed with water and dried.

The 904 bromo 155 fluoro 115,17a,21 trihydroxypregn 4 ene 3,20 dione 21-acetate (0.55 g.) so obtained was dissolved in 15 ml. of acetone and heated under reflux with 0.6 -g. of potassium acetate for 24 hrs. The resulting mixture was evaporated to dryness and the residue was shaken with a mixture of water and methylene chloride. The methylene chloride layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The dried solution was filtered and the filtrate was evaporated to dryness. The residue (0.486 g.) Was dissolved in methylene chloride and chromatographed on a column of magnesium silicate (Florisil). The column was eluted with Skellysolve B containing 12.5% by volume of acetone and those fractions which, on the basis of paper chromatographic analysis, were shown to contain the desired product, were combined and evaporated to dryness. There Was thus obtained 0.359 g. of 155- fiuoro 1711,21 dihydroxy 95,115 oxidopregn 4 ene- 3,20 dione 21-acetate in the form of a crystalline solid having am-elting point of 205 to 207 C.

Using the above procedure, but replacing l55-fluoroll5,l7a,21 trihydroxypregn 4 ene 3,20 dione 2lacetate by the 2l-acetates or other 21-acylates of 155- fiuoro 6oz methyl 115,17a,21 trihydroxypregn 4- ene 3,20 dione or 6a,155 difluoro l15,17a,21 trihydroxypregn 4 ene 3,20 dione, there are obtained the corresponding 2l-acylates of 155 fluoro 6a methyl 1711,21 dihydroxy 95,115 oxidopregn 4 ene- 3,20 dione, and 60 ,155 difluoro 17a,2l dihydroxy- 95,l15 oxidopregn 4 ene 3,20 dione, respectively.

EXAMPLE 11 A solution of 0.35 g. of 155-fiuoro-17a,2l-dihydroxy- 95,115oxipregn-4-ene-3,20-dione 21-acetate in 3.5 m1. of methylene chloride was cooled to 70 C. and added to a mixture of 3 g. of anhydrous hydrogen fluoride and 53 ml. of tetrahydrofuran at -20 C. The mixture was allowed to stand for 16 hours at -20 C. and then for 4 hrs. at +5 C. before being poured into a stirred ice-cold solution of 21.6 g. of sodium bicarbonate in 100 ml. of water. The resulting mixture was extracted with ethyl acetate and the organic extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to dryness and the residue was recrystallized twice from a mixture of acetone and Skellysolve B. There was thus obtained 110 mg. of 90,155-difluoro 11,3,l7oc,21 trihyroxypregn-4-ene-3,20-dione 21- acetate in the form of a crystalline solid having a melting point of 213 to 214 C., with decomposition. The ultra violet spectrum of this compound (in ethanol solution) exhibited a maximum at 238 millimicrons.

Analysis.-Calcd. for C H F O C. 62,71; H, 6.87; F, 8.63. Found: C, 63.02; H, 6.85; F, 8.12.

Using the above procedure, but replacing 155-fluoro- 17a,2l-dihydroxy-95,115-oxidopregn-4-ene-3,ZO-dione 21- acetate by the 21-acetates or other 21-acylates of 155- fluoro 6a methyl-171131-dihydroxy-95,115-oxidopregn- 4-ene-3,20-dione or 6a,155-difluoro-l7a,2l-dihydroxy-95, 115-oxidopregn-4-ene-3,20-dione, there are obtained the corresponding 21-acylates of 9a,155-difluoro-6a-methyl- 115,17a,21-trihydroxypregn-4-ene-3,20-dione and 60:,911, 155-trifluoro-115,17a,21-trihydroxypregn-4-ene 3,20-dione, respectively.

EXAMPLE 12 9oz,155-Difluor0-115,1 7a,21-Trihydr0xy-1,4-Pregnadiene- 3,20-Dine 21-Acetate A mixture of 300 mg. of 9a,155-difiuoro-115,17u,21-trihydroxypregn-4-ene-3,20-dione 2l-acetate, 40 ml. of tbutyl alcohol, 0.4 ml. of acetic acid, and 150 mg. of selenium dioxide was heated under reflux for 44 hrs. An additional 150 mg. of selenium dioxide was then added and the mixture was heated for an additional 19 hrs. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and the solution so obtained was washed successively with cold aqueous sodium bicarbonate solution, aqueous ammonium polysulfide solution, dilute ammonium hydroxide solution, water, dilute hydrochloric acid, and water. The Washed solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was dissolved in methylene chloride containing by volume of acetone and chromatographed on a column of 100 g. of magnesium silicate (Florisil). The column was eluted with 1.5 l. of methylene chloride containing 7.5% by volume of acetone followed by 750 ml. of methylene chloride containing 12.5% of acetone. The eluate obtained was evaporated to dryness and the residue (200 mg. was recrystallized twice from a mixture of acetone and Skellysolve B. There was thus obtained 60 mg. of 90;,155 difiuoro 115,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione 21 acetate in the form of a crystalline solid having a melting point of 232 to 233 C., with decomposition. The ultraviolet spectrum of the compound (in ethanol solution) exhibited a maximum at 238 millimicrons (e=16,000). The infrared spectrum of the compound (mineral oil mull) exhibited maxima at 3560, 3470, 3330, 1750, 1740, 1710, 1665, 1625, 1608, 1230, and 1215 reciprocal centimeters.

Analysis.Calcd. for C H F O C, 63.00; H, 6.44;

F, 8.67. Found: C, 63.26; H, 6.24; F, 8.62.

EXAMPLE 13 9u,155-Difluoro-115,1701,21-Irihydroxy-1,4-Pregnadiene- 3,20-Di0ne Using the procedure described in Example 6, but replacing 155 fluoro 115,17a,21 trihydroxypregn-4-ene- 3,20-dione 21-acetate by 9u,155-difluoro-115,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate, there is obtained 9u,155-difiuoro-l15,-17m,2l trihydroxy-lA-pregnadiene-3,20-dione.

Using the procedure described in Example 7, but replacing 155 fluoro 1l5,17u,21-trihydroxypregn-4-ene 3, 20-dione by 9a,155-difluoro-115,17a,21-trihydroxy-1,4- pregnadiene-3,20-dione, there is obtained 9a,l55-difiuo'ro- 115,l7a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-propionate.

Similarly, by reacting 9a,155-difluoro-115,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione with the appropriate acid anhydride or acid halide in the presence of pyridine there are obtained the corresponding 2l-acylate's such as the 21-benzoate, 21-isobutyrate, 2l-valerate, 21-hexanoate, 21-trimethylacetate, 21-5-cyclopentylpropionate, 21- hemisuccinate, 21-glutarate, and the like.

EXAMPLE 15 9a,15,B-Dl'flu0r0-1 15,1 7 04,21 -Trihydroxy-1,4-Pregnadiene- 3 ,2 0-D ione 21 -Methanesulfonate A solution of 1 g. of 9a,155-difluoro-115,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione in 7 ml. of pyridine is cooled to 0 C. and treated with 0.3 ml. of methanesulfonyl chloride. The resulting mixture is allowed to stand at 0 C. to 5 C. for several hours and is then diluted with water and extracted three times with methylene chloride. The methylene chloride extracts are combined, washed with an excess of dilute hydrochloric acid, then with aqueous sodium bicarbonate solution, and finally with water. The washed solution is dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated to dryness. There is thus obtained the 2l-methanesulfonate of ,155 difiuoro 115,17 11,21-trihydroxy-1,4-pregnadiene-3,20-dione.

Using the above procedure, but replacing 9a,155-difluoro-l 15,17oc,21-trihydroxy-1,4-pregnadiene-3,20-dione by 9a,155-difluoro-115,17u,21-trihydroxypregn-4-ene-3-20- dione,

-fiu0ro-115,17a,21-trihydroxypregn-4-ene-3,20-dione,

155-fluoro-1 15,17a,21-trihydroxy-1,4-pregnadiene-3 ,20-

dione,

155-fluoro-6u-methyl-115,17a,21-trihydroxy-1,4-

pregnadiene-3,20-dione,

60:,155-(11111101'0-1 15,17,21-trihydroxypregn-4-ene-3 ,20-

dione,

6a,l55-difiuoro-115,17a,21-trihydroxy-1,4-

pregnadiene-3,20-dione,

60,9oc, 1 55-trifluoro-115,17a,21-trihydroxypregn-4-ene- 3,20-dione,

6u,9a,155-trifiuoro-115,17a,21-trihydroxy-1,4-

pregnadiene-3 ,20-dione,

6a-methyl-9u,155-difluoro-115,17a,21-trihydroxypregn- 4-ene-3,20-dione, or

6a-methyl-9ot,155-difluoro-115,17a,21-trihydroxy-1,4-

pregnadiene-3 ,ZO-dione there are produced the 21-methanesulfonates of these compounds.

EXAMPLE 16 To a solution of 1 g. of 90:,155-difl11010-11B,17oz,21- trihydroxy-1,4-pregnadiene-3,20-dione 21-methanesulfonate in 15 ml. of acetone is added a solution of 1 g. Of sodium' iodide in 10 ml, of acetone. The mixtur so obtained is heated under reflux for a short period and is then concentrated under reduced pressure to about onethird volume. Ice water is added to the concentrate and the solid which separates is isolated by filtration, washed with water and dried. There is thus obtained 90:,155-

"1% difluoro '11[3,17cc dihydroxy 21 iodo-1,4-pregnadiene- 3,20-dione.

Using the above procedure, but using as starting materials the ZI-methanesulfonates of 9a,155-difluoro-115,17a,2l-trihydroXypregn-4-ene-3 ,20-

dione, 155-fiuoro115,1701,21-trihydroxypregn-4-ene-3 ,ZO-dione,

7 1S -fluoro1 l 5,17a,21-trihydroxy-1,4-pregnadiene-3,20-

dione,

155-fiuoro-6a-methyl-1 15, 1711,21-trihydroXypregn-4-ene- 3,20-dione, 155-fluoro-6a-rnethyl-115,17a,21-trihydroXy-1,4-pregnadiene-3 ,ZO-dione, 6a,155-difluoro-ll5,1704,2l-trihydroxypregn-4-ene-3 ,20-

dione, 1 5 60:,15/3-difll1010-1 15,1704,2l-trihydroxy-l,4-pregnadiene- 3 ,ZO-dione, 601,911, 155-trifluoro-1 l5,170:,2l-trihydr0Xypregu-4-ene- 3 ,ZO-dione, 6a,9a,155-trifluoro-1l5,17 x,2l-trihydroxy-lA-pregnadiene-3,20-dione, 6u-methyl-9u,155-difluoro-115,17a,21-trihydroxypregn- 4-ene-3,20-dione, or 6a-methyl-9a,155-difiuoro-115,l7a,21-trihydroXy-1,4-

pregnadiene-3,20-dione there are produced 90:,15B-difl110I0-1 15,17a-dihydroxy-21-iodopregn-4-ene- 3 ,20-dione, 155-fluoro-115,17a,dihydroxy-21-iodopregn-4-ene-3,20-

dione, 155-fluoro-115,17u-dihydroxy-21-iodo-1,4-pregnadiene- 3 ,20-dione, 155-fluoro-6a-methyl-115,17a-dihydroxy-21-iodopregn- 4-ene-3 ,ZO-dione, 7 155-fluoro-6a-methyl-1 15,17a-dihydroxy-2l-iodo-1,4-

pregn adiene-3 ,ZO-dione, 60:,15B-difiLlOIO-11B,I'I'a-dihYdIOXY-Z1-l0dO-p16g1b-4-6I1e- 3,20-dione, 6u,155-difiuoro-115,17a-dihydroxy-21-iodo-1,4-pregnadiene-3 ,20-dione, 6a,9a,155-trifluoro-115,17a-dihydroxy-21-iodopregn-4- cue-3 ,ZO-dione, 6u,9a, 15 5-triflu oro-l 15, 17oL-dlhyd1'OXY-21-iOdO-1,4-

pregnadiene-3 ,ZO-dione, 6a-methyl-9a,155-difluoro-115,17a-dihydroxy-21-iodopregn-4-ene-3,20-dione, or 6a-methyl-9a,155-difluoro-115,17m-dihydroxy-21-iodo- 1,4-pregnadiene-3,ZO-dione, respectively. EXAMPLE 17 9oc,I55-Diflu0r0-]15,I7ot-Dihydr0xy-1,4-Pregnadiene- 3,20-Dione A slurry of 150 mg. of 9a,155-difluoro-115,17a-dihydroxy-Z1-iodo-1,4-pregnadiene-3,20-dione and 150 mg. of sodium iodide in 5 ml. of acetic acid is stirred for 45 minutes before a solution of 250 mg. of sodium thiosulfate pentahydrate in 10 ml. of Water is added thereto. When the iodine color has disappeared the mixture is diluted with water and extracted with methylene chloride. The methylene chloride extract is Washed with water and then with aqueous sodium bicarbonate solution before being dried over anhydrous sodium sulfate. The dried solution is filtered and the filtrate is evaporated to small .volume. The residue is chromatographed on a column of magnesium silicate (Florisil). The column is eluted with Skellysolve B containing increasing proportions of acetone and those fractions which, on the basis of paper chromatographic analysis, are shown to contain the desired product are combined and evaporated to dryness. There is thus obtained 9a,155-difiuoro-l l5,17a-dihydroxy- 1,;1:regnadiene-3,20-dione in the form of a crystalline so 1 2t) Usingthe above procedure, but using as material 9a,155-diflu0ro-1 15,17a-dihydroxy-21-iodopregn-4-ene- 3 ,ZO-dione,

15 5-fluoro-1 15,17c-dihydroxy-21-iodopregn-4-ene- 3 ,20-dione,

15 5-fluoro-1 l5,17a-dihydroxy-21-iodo-1,4-pregnadiene- 3 ,20-dione,

15,8-fiuOrO-6oz-II161IhYl-l 15,17a-dihydroxy-2l-iodopregn- 4-ene-3 ,20-dione,

155-fiuoro-6a-methyl-115,17a-dihydroxy-21-iodo-1,4-

pregnadiene-3 ,ZO-dione,

60,155-difit10fO-1 15,17a-dihydroxy-21-iodopregn-4-ene- 3,20-dione,

60:,155-CllflUOIO-1 15,17a-dihydroXy-21-iodo-1,4-pregnadiene-3,20-dione,

60:,911,155-trifluoro-l15,17oz-dihydroXy-21-iodopregn-4- ene-3 ,20-dione,

6a,9a,155-trifluoro-115,17m-dihydroxy-21-iodo-1,4-pregnadiene-3,20-dione,

pregn-4-ene-3,20-dione, or

6oc-methyl-9oc, 15 5-difiuoro-1 15,17a-dihydroxy-21-iodo- 1,4-pregnadiene-3 ,20-dione,

there are obtained 9oz, 155-difluoro-1 15,17a-dihydroxypregn-4-ene-3,20-

dione,

155-fluoro-1 15,17a-dihydroXypregn-4-ene-3 ,20-dione,

155-fluoro-1l5,17a-dihydroxy-1,4-pregnadiene-3,20-

dione,

l55-fiuoro-6ot-methy1-1 15,17oc-dihydroxypregn-4-ene- 3,20-dione,

6oz,155-difluoro115,17a-dihydroxypregn-4-ene-3,20-

dione,

60,15/3-difll1010-1 15,17a-dihydroxy-1,4-pregnadiene-3,20-

dione,

dione,

601,9, 155-trifluoro-1 15,17u-dihydroxy-1,4-pregnadiene- 3,20-dione,

6a-methyl-9a, 15 5-difluoro-1 15,17a-dihydroxypregn-4- cue-3,20-dione, and

6a-rnethyl-9a,155-difluoro-1'15,17u-dihydroxy-1,4-pregnadiene-3,20-dione,

respectively.

EXAMPLE 18 9a,155-Diflu0r0-115,1 7u-Dihydroxy-1,4-Pregnadiene- 3,11,20-Tri0ne Using the procedure described in Example 8, but replacing 155-fluoro-115,17a,21-trihydroxypregn-4-ene-3,20- tdione 2l-acetate by 9a,155-difluoro-1l5,17u-dihydroxy- '1,4-pregnadiene-3,20-dione, there is obtained :,155-difluoro-17a-hydroxy-1,4-pregnadiene-3, 1 1,20-trione.

Similarly 9m,155-difluoro-115,17a-dihydroxypregn-4-ene-3,20-

dione,

-fluoro-115,17a-dihydroxypregn-4-ene-3 ,ZO-dione,

155-fluoro-1 15,17a-dihydroxy-1,4-pregnadiene-3,20-

dione,

15 5-fluoro-6 a-methyl-l 15,17u-dihydroxypregn-4-ene-3 ,20-

dione,

15 5-fluoro-6a-methyl-1 15,17a-dihydroxy-1,4-pregnadienestarting are oxidized to the corresponding 11-oxo compounds.

EXAMPLE 19 To a solution of 1 g. of 9a,15)3-difl\10rO-11B,17a-dihydroxy-l,4-pregnadiene-3,20dine in 15 ml. of acetic acid is added 4 ml. of acetic anhydride. The mixture is purged with nitrogen and cooled whilst 0.4 g. of ptoluene-sulfonic acid is added. The reaction mixtur is allowed to stand for several hours and then poured into ice water. The solid which separates is isolated by filtration, washed with Water, and recrystallized from aqueous methanol. There is thus obtained 9a,15/3-diflu010- 115,170 dihydroxy 1,4 pregnadiene 3,20 dione 17- acetate in the form of a crystalline solid.

Using the above procedure but replacing acetic anhydride by the appropriate acid anhydride there are obtained other 17-acylates of 9a,l5fl-difluoro-1lfi,l7a-dihydroxy-1,4-pregnadiene-3,20-dione.

Similarly, using the above procedure but replacing 90:,156 difluoro 115,17a dihydroxy-lA-pregnadiene- 3,20-dione by 90,l5fi difluoro-l1[3,l7udihydroxypregn- 4-ene-3,20-dione, 15,8 fluoro 1lfi,17a-dihydroxypregn-4- ene-3,20-dione, 15B fluoro 115,17u dihydroxy-1,4- pregnadiene-3,20-dione, 15p fluoro-6a-methyl 11}9,17adihydroxypregn-4-ene-3,ZO-dione, 15,8 fluoro-6a-methyl- 1113,17 dihydroxy-l,4-pregnadiene-3,ZO-dione, 60:,1518- difluoro-llfi,l7u-dihydroxypregn 4 ene 3,20 dione, 6a,15;3-difluoro-11;8,l7a-dihydroxy 1,4 pregnadiene- 3,20-dione, 6a,9a,15/8-trifluoro-l 15, l7a-dihydroxypregn-4 ene-3,20-dione, 6a,9a,15fl trifluoro-l1;8,17a-dihydroxy- 1,4-pregnadiene 3,20 dione, 6a-methyl-9oz,ISB-difluoro- 11,3,l7a-dihydroxypregn-4-ene-3,20 dione, 6a-methyl- 9a,1518-difluoro 115,17 dihydroxy-l,4-pregnadiene- 3,20-dione or the corresponding ll-oxo derivatives of the above-named compounds there are obtained the corresponding 17-acetates and like 17-acylates of the above compounds.

wherein the bond between carbon atoms 1 and 2 is selected from the class consisting of single and double bonds, R is selected from the class consisting of hydrogen, hydroxy, and acyloxy, R represents hydroxy and, when R represents hydrogen, R additionally represents a group selected from the class consisting of hydrogen and acyloxy, X is selected from the class consisting of hydrogen and fluorine, Y is selected from the class consisting of hydrogen, fluorine, and methyl, 'and Z is selected from the class consisting of B-hydroxymethylene and carbonyl, and wherein the acyl of the acyloxy group in each instance is that of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive.

2. l5B-fluoropregn-4-ene-3,11,20-trione.

3. 15;8-fluoro-11B,17a,21 trihydroxypregn-4-ene-3,20- dione.

4. 15B fluoro-11,3,l7a,21-trihydroxypregn-4-ene-3,20- dione 21-acetate.

5. 15B fluoro-11,8,170:,2l-trihydroxy-lA-pregnadriene- 3,20-dione.

6. 155 fluoro-1118,17a,21-trihydroxy-1,4-pregnadiene- 3,20-dione ZI-acetate.

No references cited. 

1. A 15B-FLUORO COMPOUND HAVING THE FORMULA 